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Abstract Background Despite the close relationship between sleep–wake cycles and depression symptoms, the relationship between sleep midpoint and depression symptoms in adults remains understudied. Methods In this cross-sectional study, 18280 adults aged ≥ 18 years from the National Health and Nutrition Examination Survey (NHANES) 2015–2020 were analyzed. Covariates included age, sex, race/ethnicity, education level, marital status, family income, body mass index, smoking status, drinking status, physical activity, comorbid condition, sleep duration, and sleep disturbance were adjusted in multivariate regression models. Results Weighted restricted cubic spline based on the complex sampling design of NHANES showed that in participants with a sleep midpoint from 2:18 AM to 6:30 AM, the prevalence of depression symptoms increased by 0.2 times (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.08–1.33) per 1-h increment in sleep midpoint compared to the reference point of 2:18 AM. For participants with a sleep midpoint after 6:30 AM and before 2:18 AM the next day, the relationship between sleep midpoint and depression symptoms was not significant after adjusting for all covariates (adjusted OR = 1.01, 95% CI: 0.99–1.03). Conclusions The findings indicate a significant nonlinear association between sleep midpoint and depression symptoms in a nationally representative sample of adults.